Type I Diabetes induced by OT-I T-Cells requires ITK-mediated TCR signaling.

Abstract

Abstract Activation of CD8+ T-cells induces changes in T cell trafficking, promoting effector T cell migration into tissues. ITK, a tyrosine kinase activated by TCR signaling, has previously been shown to be required for CD8+ T cell migration into the gastrointestinal tract during viral infection. This finding prompted us to investigate whether ITK signaling was important for effector T cell trafficking into non-infected tissue, as might occur in autoimmune disease. Using the RIP-mOVA mouse model, in which the OVA protein is expressed in the β-islet cells of the pancreas, we examined the ability of WT versus ITK-deficient OT-I T cells to infiltrate the pancreas inducing Type I diabetes. To test this, WT or ITK-deficient OT-I cells were adoptively transferred into RIP-mOVA recipients. Mice were immunized with OVA peptide plus LPS, and monitored for urine glucose. We also examined OT-I cell numbers in the pancreatic draining lymph node and in the pancreas 72hr post-immunization. We found that in the absence of ITK, OT-I cells were impaired in their ability to induce diabetes, with only ~1/3 of the recipients progressing to disease; in contrast 100% of recipients receiving WT OT-I cells developed Type I diabetes. In addition, the numbers of infiltrating ITK-deficient OT-I cells in the pancreas was significantly reduced compared to the numbers of WT OT-I cells detected. These findings indicate that ITK has a key role in generating pathogenic tissue-infiltrating CD8+ T cells capable of migration into β-islets of the mouse pancreas. While exploration of the mechanism underlying this impaired migration needs further investigation, these data provide support for therapeutic potential of an ITK inhibitor in patients with tissue-specific autoimmune diseases. Supported by NAID TRC SIGNLG